Glutaminolysis and fumarate accumulation integrate immunometabolic and epigenetic programs in trained immunity

Induction of trained immunity (innate immune memory) is mediated by activation of immune and metabolic pathways that result in epigenetic rewiring of cellular functional programs. Through network-level integration of transcriptomics and metabolomics data, we identify glycolysis, glutaminolysis, and the cholesterol synthesis pathway as indispensable for the induction of trained immunity by ß-glucan in monocytes. Accumulation of fumarate, due to glutamine replenishment of the TCA cycle, integrates immune and metabolic circuits to induce monocyte epigenetic reprogramming by inhibiting KDM5 histone demethylases. Furthermore, fumarate itself induced an epigenetic program similar to ß-glucan-induced trained immunity. In line with this, inhibition of glutaminolysis and cholesterol synthesis in mice reduced the induction of trained immunity by ß-glucan. Identification of the metabolic pathways leading to induction of trained immunity contributes to our understanding of innate immune memory and opens new therapeutic avenues.Netherlands Organization for Scientific Research (NWO). B.N. is supported by an NHMRC (Australia) CJ Martin Early Career Fellowship. N.P.R. Netherlands Heart Foundation (2012T051). N.P.R. and M.G.N. received a H2020 grant (H2020-PHC-2015-667873-2) from the European Union (grant agreement 667837). Fundação para a Ciência e Tecnologia, FCT (IF/00735/2014 to A.C., IF/00021/2014 to R.S., RECI/BBB-BQB/0230/2012 to L.G.G., and SFRH/BPD/96176/2013 to C. Cunha). The NMR spectrometers are part of the National NMR Facility supported by FCT (RECI/BBB-BQB/0230/2012). The research leading to these results received funding from the Fundação para a Ciência e Tecnologia (FCT), cofunded by Programa Operacional Regional do Norte (ON.2—O Novo Norte); from the Quadro de Referência Estratégico Nacional (QREN) through the Fundo Europeu de Desenvolvimento Regional (FEDER) and from the Projeto Estratégico – LA 26 – 2013–2014 (PEst-C/SAU/LA0026/2013). NIH (DK43351 and DK097485) and Helmsley Trust. D.L.W. is supported, in part, by the NIH (GM53522, GM083016, GM119197, and C06RR0306551

Four top quark production searches and cross section measurements at the LHC

Four top quark production is a rare standard model that has been observed for the first time in proton-proton collisions at $\sqrt{s} = 13$\,TeV at the CERN LHC by both the ATLAS and CMS Collaborations. Both observations were made in the same-sign dilepton and multilepton final states of the process and are presented in this contribution. In addition, another measurement of four top production by the CMS Collaboration using the all hadronic, one lepton and opposite-sign dilepton final states is presented. This is the first result to take a direct look at the all hadronic final state.Four top quark production is a rare standard model process that has been observed for the first time in proton-proton collisions at \sqrts at the CERN LHC by both the ATLAS and CMS Collaborations. Both observations were made in the same-sign dilepton and multilepton final states of the process and are presented in this contribution. In addition, another measurement of four top production by the CMS Collaboration using the all hadronic, one lepton and opposite-sign dilepton final states is presented. This is the first result to take a direct look at the all hadronic final state

Aberglauben, Krankheit und das Böse. Exorzismus und Teufelsglaube im 18. und 19. Jahrhundert

peer reviewe

Prevalence and associated risk factors of HIV infections in a representative transgender and non-binary population in Flanders and Brussels (Belgium) : protocol for a community-based, cross-sectional study using time-location sampling

IntroductionHIV prevalence and sexual risk have been estimated very high for transgender people. However, the limited sampling and data collection methods used in current research on transgender people potentially led to overrepresentation and generalisation of people at risk for HIV. Current HIV prevalence estimates in transgender populations are generalised from studies mainly focusing on transgender women engaging in sex work. Moreover, studies focusing on non-binary people, who identify with a broad range of identities beyond the traditional male and female gender identities, are scarce. ObjectivesTo estimate the HIV prevalence rate in the Flemish and Brussels (Belgium) transgender population, including transgender women, transgender men and non-binary people, and to identify the associated risk factors. MethodsIn this community-based cross-sectional study, self-identified transgender and non-binary (TGNB) people will be recruited through a two-stage time-location sampling approach. First, community settings in which TGNB people gather will be mapped to develop an accurate sampling frame. Secondly, a multistage sampling design is applied involving a stratification based on setting type (healthcare facilities vs outreach events), a selection of clusters by systematic sampling and a simple random selection of TGNB people within each cluster. Participants will complete an electronic self-reported survey to measure sociological, sexual and drug-using behaviors (risk factors) and oral fluid aliquots will be collected and tested for HIV antibodies. Logistic regression models will be used to evaluate risk factors independently associated with HIV infection. The presented study is registered at ClinicalTrials.gov (NCT04930614). DiscussionThis study will be the first to investigate the HIV prevalence rates and associated risk behaviors in an accurate representation of the TGNB population in a Western European country. The findings will globally serve as a knowledge base for identifying subgroups at risk for becoming infected with HIV within TGNB people and to set up targeted prevention programs. Discussion This study will be the first to investigate the HIV prevalence rates and associated risk behaviors in an accurate representation of the TGNB population in a Western European country. The findings will globally serve as a knowledge base for identifying subgroups at risk for becoming infected with HIV within TGNB people and to set up targeted prevention programs

Oxidized Phospholipids on Lipoprotein(a) Elicit Arterial Wall Inflammation and an Inflammatory Monocyte Response in Humans

Elevated lipoprotein(a) [Lp(a)] is a prevalent, independent cardiovascular risk factor, but the underlying mechanisms responsible for its pathogenicity are poorly defined. Because Lp(a) is the prominent carrier of proinflammatory oxidized phospholipids (OxPLs), part of its atherothrombosis might be mediated through this pathway. In vivo imaging techniques including magnetic resonance imaging, (18)F-fluorodeoxyglucose uptake positron emission tomography/computed tomography and single-photon emission computed tomography/computed tomography were used to measure subsequently atherosclerotic burden, arterial wall inflammation, and monocyte trafficking to the arterial wall. Ex vivo analysis of monocytes was performed with fluorescence-activated cell sorter analysis, inflammatory stimulation assays, and transendothelial migration assays. In vitro studies of the pathophysiology of Lp(a) on monocytes were performed with an in vitro model for trained immunity. We show that subjects with elevated Lp(a) (108 mg/dL [50-195 mg/dL]; n=30) have increased arterial inflammation and enhanced peripheral blood mononuclear cells trafficking to the arterial wall compared with subjects with normal Lp(a) (7 mg/dL [2-28 mg/dL]; n=30). In addition, monocytes isolated from subjects with elevated Lp(a) remain in a long-lasting primed state, as evidenced by an increased capacity to transmigrate and produce proinflammatory cytokines on stimulation (n=15). In vitro studies show that Lp(a) contains OxPL and augments the proinflammatory response in monocytes derived from healthy control subjects (n=6). This effect was markedly attenuated by inactivating OxPL on Lp(a) or removing OxPL on apolipoprotein(a). These findings demonstrate that Lp(a) induces monocyte trafficking to the arterial wall and mediates proinflammatory responses through its OxPL content. These findings provide a novel mechanism by which Lp(a) mediates cardiovascular disease. URL: http://www.trialregister.nl. Unique identifier: NTR5006 (VIPER Study

First evidence for off-shell production of the Higgs boson and measurement of its width

The first evidence for off-shell Higgs production is reported in the final state with two Z bosons decaying into either four charged leptons (muons or electrons), or two charged leptons and two neutrinos, and a measurement of the Higgs boson width is performed. Results are based on data from the CMS experiment at the LHC at a center-of-mass energy of 13 TeV, corresponding to an integrated luminosity of up to 140 fb$^{-1}$. The total rate of off-shell Higgs boson production beyond the Z boson pair production threshold, relative to its standard model expectation, is constrained to the interval [0.0061, 2.0] at 95% confidence level. The scenario with no off-shell production is excluded at 99.97% confidence level (3.6 standard deviations). The width of the Higgs boson is extracted as $\Gamma_{\mathrm{H}}$ = 3.2$_{-1.7}^{+2.4}$ MeV, in agreement with the standard model expectation of 4.1 MeV. The data are also used to set new constraints on anomalous Higgs boson couplings to W and Z boson pairs

First evidence for off-shell production of the Higgs boson and measurement of its width

The first evidence for off-shell Higgs production is reported in the final state with two Z bosons decaying into either four charged leptons (muons or electrons), or two charged leptons and two neutrinos, and a measurement of the Higgs boson width is performed. Results are based on data from the CMS experiment at the LHC at a center-of-mass energy of 13 TeV, corresponding to an integrated luminosity of up to 140 fb$^{-1}$. The total rate of off-shell Higgs boson production beyond the Z boson pair production threshold, relative to its standard model expectation, is constrained to the interval [0.0061, 2.0] at 95% confidence level. The scenario with no off-shell production is excluded at 99.97% confidence level (3.6 standard deviations). The width of the Higgs boson is extracted as $\Gamma_{\mathrm{H}}$ = 3.2$_{-1.7}^{+2.4}$ MeV, in agreement with the standard model expectation of 4.1 MeV. The data are also used to set new constraints on anomalous Higgs boson couplings to W and Z boson pairs

Azimuthal correlations in Z+jets events in proton-proton collisions at s\sqrt{s} = 13 TeV

The production of Z bosons associated with jets is measured in pp collisions at $\sqrt{s}=$ 13 TeV with data recorded with the CMS experiment at the LHC corresponding to an integrated luminosity of 36.3 fb$^{-1}$. The multiplicity of jets with transverse momentum $p_{\mathrm{T}} >$ 30 GeV is measured for different regions of the Z boson's $p_{\mathrm{T}}(\mathrm{Z})$, from lower than 10 GeV to higher than 100 GeV. The azimuthal correlation $\Delta \phi$ between the Z boson and the leading jet, as well as the correlations between the two leading jets are measured in three regions of $p_{\mathrm{T}}(\mathrm{Z})$. The measurements are compared with several predictions at leading and next-to-leading orders, interfaced with parton showers. Predictions based on transverse-momentum dependent parton distributions and corresponding parton showers give a good description of the measurement in the regions where multiple parton interactions and higher jet multiplicities are not important. The effects of multiple parton interactions are shown to be important to correctly describe the measured spectra in the low $p_{\mathrm{T}}(\mathrm{Z})$ regions.The production of Z bosons associated with jets is measured in $\text {p}\text {p}$ collisions at $\sqrt{s}=13\,\text {Te}\hspace{-.08em}\text {V}$ with data recorded with the CMS experiment at the LHC corresponding to an integrated luminosity of 36.3$\,\text {fb}^{-1}$. The multiplicity of jets with transverse momentum $p_{\textrm{T}} > 30\,\text {Ge}\hspace{-.08em}\text {V}$ is measured for different regions of the Z boson’s $p_{\textrm{T}} (\text {Z })$, from lower than 10$\,\text {Ge}\hspace{-.08em}\text {V}$ to higher than 100$\,\text {Ge}\hspace{-.08em}\text {V}$. The azimuthal correlation $\varDelta \phi$ between the Z boson and the leading jet, as well as the correlations between the two leading jets are measured in three regions of $p_{\textrm{T}} (\text {Z })$. The measurements are compared with several predictions at leading and next-to-leading orders, interfaced with parton showers. Predictions based on transverse-momentum dependent parton distributions and corresponding parton showers give a good description of the measurement in the regions where multiple parton interactions and higher jet multiplicities are not important. The effects of multiple parton interactions are shown to be important to correctly describe the measured spectra in the low $p_{\textrm{T}} (\text {Z })$ regions.The production of Z bosons associated with jets is measured in pp collisions at $\sqrt{s}$ = 13 TeV with data recorded with the CMS experiment at the LHC corresponding to an integrated luminosity of 36.3 fb$^{-1}$. The multiplicity of jets with transverse momentum $p_\mathrm{T}$$\gt$ 30 GeV is measured for different regions of the Z boson's $p_\mathrm{T}$(Z), from lower than 10 GeV to higher than 100 GeV. The azimuthal correlation $\Delta \phi$ between the Z boson and the leading jet, as well as the correlations between the two leading jets are measured in three regions of $p_\mathrm{T}$(Z). The measurements are compared with several predictions at leading and next-to-leading orders, interfaced with parton showers. Predictions based on transverse-momentum dependent parton distributions and corresponding parton showers give a good description of the measurement in the regions where multiple parton interactions and higher jet multiplicities are not important. The effects of multiple parton interactions are shown to be important to correctly describe the measured spectra in the low $p_\mathrm{T}$(Z) regions